9 alpha-halo-16-dehydro steroids of the pregnane series



United States Pateno 9a-HALO-16-DEHYDRO STEROIDS OF THE PREGNANE SERIES Gordon H. Thomas and Josef Fried, New Brunswick,

NJ., assignors to Olin Mathieson Chemical Corporation, New York, N.Y., a corporation of Virginia No Drawing. Filed June '5, 1957, Ser. No. 663,597

Claims. (Cl. 260-39745) This invention relates to the synthesis of steroids and has for its objects: (1) the provision ofan advantageous process of preparing physiologically active steroids of the 9u-halo-A -pregnadiene series; and (2) the provision of certain new steroids useful either for their own pregnadiene-l'lfifl1-diol-3,20-dione'- and deketalizing to form "a 9a-halo-A -pregnadiene 11fl,2l-diol-3,20-dione.

The novel compounds of this invention comprise: (A) the 3,20-diketals of 9a-halocortisone which can be repre sented by the general formula wherein A is a divalent organic radical, such as lower alkylcne (e.g., ethylene, propy1ene 1,2 and propylene- 1,3), X is halogen (preferably chlorine and fluorine), and Y is hydrogen or an acyl radical, especially the acyl radical of a hydrocarbon carboxylic acid having less than ten carbon atoms, as exemplified by the acyl radicals of the lower alkanoic acids (e.g., acetic, propionic and butyric acid), the monocyclic aryl carboxylic acids (e.g., benzoic and toluic acid), the monocyclic aryl lower alkanoic acids (e.g., phenacetic and B-phenyl-propionic acid), the lower alkenoic acids, the cycloalkanecarboxylic acids and the cycloalkenecarboxylic acids; and (B) the 9a-halo-A -steroids of the general formula wherein one of the positions 4,5 and 5,6 is double-bonded, R and R together are either keto or -O--A--O, wherein A is as hereinbefore defined, R" is hydrogen, R' is B-hydroxy or together R" and R' is keto, and X and Y are as hereinbefore defined.

Compounds of Formula B, wherein the double-bond is in the 4,5-position and R and R together are keto,are new physiologically active steroids which possess glucocorticoid activity and hence can be employed in lieu of known glucocorticoids such as hydrocortisone or cortisone in the treatment of rheumatoid arthritis, for which purpose they can be administered in the same manner as hydrocortisone, for example, the dosage being adjusted for the relative potency of the particular steroid.

The process of this invention can be represented by the following scheme:

2,963,496 Patented Dec. 6, 1960 VII X=F VIII X=Cl CHzOH To prepare Compounds B, a 9a-halocortisone (e.g., 9a-fluorocortisone and 9a-chlorocortisone) is diketalized by treatment with an excess of a glycol, A(OH) (e.g., ethylene glycol and propylene glycol). This reaction is preferably conducted at an elevated temperature in the presence of a strong acid catalyst (e.g., p-toluenesulfonic acid). The reaction results in the formation of the 3,20- diketal (Compounds Aa), wherein the ketalizing group corresponds to the glycol used in the preparation.

The diketal, Compound Aa, is then esterified in the usual manner, as by treatment with an acyl halide, BX, or acid anhydride, BOB, wherein B represents the acyl radical of an acid, especially a hydrocarbon carboxylic acid having less than ten carbon atoms (e.g., acetic anhydride). This reaction is preferably carried out in the presence of an organic base, suchas pyridine, and yields the 21-ester of the starting diketal (Compounds Ab).

Compound Ab is then treated with thionyl chloride to yield the 16-dehydro derivative. This reaction is preferably conducted in the cold in the presence of an organic base, such as pyridine. The initial product formed is the 3,20-diketal 21-ester of 9whale-A -pregnadiene-Zl-ol 3,11,20-trione (Compounds Ba), which can then be deketalized, as by heating with a dilute acid (e.g., dilute sulfuric acid), the reaction preferably being carried out in an organic solvent (e.g., methanol) wherein the diketal is soluble. The reaction results in the formation of a 9a-halo-A -pregnadiene 21 ol 3,11,20-trione (Compounds Bb), wherein the initial reactant has not only been deketalized but also hydrolyzed with the removal of the 21-esterifying group. 'If a 21-ester is desired, the resulting compound can be esterified by the procedure described, above to yield the 21-ester.

Compounds Ba can alsobe reduced, as by treatment with an alkali metal borohydride (e.g., lithium borohydride or sodium borohydride), the reaction preferably being conducted in an organic solvent such as tetrahydrofuran to yield the corresponding, 3,20=diketal of 9a-halo- 90t-flI1OI'OCOIIlSOIl6 1n the procedure of Example 1, there IS A pregnadiene-l1fl,21-diol-3,20-dione- (Compounds Bd), which can then be deketalized as above described to yield a:- 9a.-halo-A -pregnadiene-115,21-dio1-3,20-dione (Compound Bc) The following examples illustrate the invention (all temperatures being in centigrade).

EXAMPLE 1 9au0r0-A -pregnene-1 7u,21-di0l-3,11 ,ZO-trione 3,20 bis-ethylene ketal (I) A mixture of 9a-fiuorocortisone (15 g.), ethylene glycol (120 ml.), benzene (525 ml.) and p-toluenesulfonic acid monohydrate (240 mg.) is refluxed for 24 hours, the water formed during the reaction being removed azeotropically in a suitable separator. After concentrating the mixture in vacuoto'half, itsvolume, it is Washed successively with dilute sodium bicarbonate solution and Water, and the resulting benzene solution dried over sodium sulfate and then evaporated in vacuo. Trituration of the residue with methanol (100 ml.) yields a solid (about 10.8 g.) which melts at about 243-251". Crystallization of a sample from acetone-hexane gives the pure bisketal, M.P. about 247-251"; [ml -25.7 (c. 1.19 in CHC1 Analysis-Calculated for C H O F: C, 64.36; H, 7.56; F, 4.07. Found: C, 64.56; H, 7.35; F, 3.94.

Similarly, by substituting 9a-chlorocortisone for the obtained 9a-chloro-A -pregnene-17a,21-diol-3, l 1,20-trione 3,20-bis-ethylene ketal (II). Furthermore, if L-bl'OIIlO- cortisone or 9oc-i0dOC01'tiS0lle is substituted for 9a-fluorocortisone, the corresponding 9a-bromo and 9a-i0d0 derivatives are: formed.

EXAMPLE 2 9u-flu0ro-A -pregnene-1 7a,2l-diol-3,11,20-tri0ne 21 -acetate 3,20-bis-ethylene ketal (III) A solution of 9a-fluoro-A -pregnene-1711,21-diol-3,11,

max.

Analysis.-Calculated for C H O F: C, 63.76; H, 7.33; F, 3.74. .-Found: C, 63.80; H, 7.17; F, 3.88.

, Similarly, if 9a-chloro A -pregnne-17a,21-diol-3,11,20- trione 3,20-bis-ethylene ketal is substituted for the 9ozfluororeactant in the procedure of Example 2, 9a-chloro- A -pregnene-17u,21-dio1-3,11,20-trione 21-acetate 3,20- bis-ethylene ketal: (IV) is obtained. Furthermore, if another acylatingreagent such as propionic anhydride or benzoyl chloride issubstituted for the acetic anhydride in the procedureof Example 2, the corresponding 21-ester is I produced.

, ,'EXAMPLE 3 9u-flu0r0-A -pregnadiene-21-0l 3,11,20-trione ZI-acetate 3,20-bis-ethylene ketal (V) and 9u-fluor0-A -pregnene -16fl,21j-0xid0 -3,11,20-tri0ne 3,20-bis-ethylene ketal (a) 9a-fluor o- A -p regnene-16;6,21-0xid0-3,11,2Q-tri0ne 3,20-bis ethylene ketal: A solutionof 11 g. of 9d-fluoro- A -pregnene-17a,21-diol-3,11,20-trione Zl-acetate 3,20- bis-ethylene ketal in 70 ml. of pyridine and ml. of thionyl chloride is allowed to stand at 0 for 18 hours. The mixture is diluted with iced water and the steroids extracted with chloroform. The chloroform solution is then washed several times with water, dried over sodium sulfate and the solvent removed in vacuo to give about 10.1 g. of a yellow gum. The gum is then dissolved in benzene and absorbed on 250 g. of alumina. Elution with chloroform in benzene (10%, 500 ml.; 20%, 1.1 liters) gives about 1.69 g. of 9a-fluoro-A -pregnene-163,21- oxido-3,11,20-trione 3,20-bis-ethylene ketal.

The crude oxido compound is dissolved in ml. of benzene and absorbed on 50 g. of alumina. Elution with 1.5 liters of benzene yields a purified sample (about 962 mg.) melting at about 228-234. Crystallization from acetone-hexane gives an analytical sample (as the acetone adduct) with the following physical properties: M.P. about 233-234; [ml +29 (c. 0.53 in chloroform);

max.

Ami? 5.75, 5.79, 6.17, 8.08 ,u.

Analysis.-Calculated for C H O- F: C, 66.10; H, 7.19; F, 3.87. Found: C, 66.35; H, 6.83; F, 4.22.

(c) 90: fluoro A pregnene 165,21 oxido 3, 11,20-trione: A solution of 90 mg. of the 9Ot-fll1OIO-A pregnene 16 8,21 oxido 3,11,20 trione 3,20 bisethylene ketal obtained in section a in 5 ml. of methanol and 0.5 ml. of 8% sulfuric acid is heated under reflux for four hours. The mixture is diluted with water and the steroid extracted with chloroform. The chloroform extract is washed with water, dried over sodium sulfate and the solvent removed in vacuo. Crystallization of the residue from acetone-hexane yields a substance (about 19 mg.) melting at about 239243;

A,;, 234 my (e=12,700); Ami? 5.80, 5.97, 6.16 p

evaporated to dryness in vacuo.

my 2.87, 2.92 M

Analysis.-Calculated for C26H39O7FI C, 64.73; H, 8.15; F, 3.94. Foundz-C, 65.67; H, 8.38; F, 3.93.

Hydrolysis of this compound as described in section 0, except that the time of reflux is 1.5 hours, furnishes 9ocfl11010 {A pregnene 16 8,21 oxido 11p ol 3, 20-dione.

Similarly, by following the procedures of sections a and b ofExample 3, 9a-chloro-A -pregnene-17a,21-diol- 3,11,20-trione 21-acetate 3,20-bis-ethylene ketal yields 9m -'chloro A5,16 pregnadiene- 21 ol 3,11,20 trione 21-acetate 3,20-bis-ethylene ketal (VI).

EXAMPLE 4 Qa-flimro-Abpregnadiene-21-0l-3,11,20-trione (VII) A solution of 9oi-fluoro-A -pregnadiene-21-ol 3,11,20 trione 3,20-bis-ethylene ketal 21-acetate (100 mg.) in methanol (10 ml.) and 8% sulfuric acid (1 ml.) is refluxed for 3.5 hours. The mixture is diluted with water, extracted with chloroform and the chloroform phase washed with water, dilute sodium bicarbonate and again with water, dried over sodium sulfate and the solvent The residue on crystallization from acetone furnishes pure 9u-fluoro-A -pregnadiene-21-ol-3, 1 1,20-dione.

Similarly 9a chloro A pregnadiene 21 ol 3,11,20-trione ZI-acetate 3,20-bis-ethylene ketal can be deketalized to 9a-chloro-A -pregnadiene-21-ol-3,11,20- trione (VIII).

EXAMPLE 5 9a fluoro A pregnadiene 11 3,21 diol 3,20- dione 3,20-bis-ethylene ketal (XI) To a solution of 200 mg. of 9a-fluoro-A -pregnadiene-21-ol-3,11,20-trione 3,20-bis-ethylene ketal 21-acetate in tetrahydrofuran (10 ml.) is added 200 mg. of lithium borohydride and the resulting mixture stirred for 18 hours at room temperature. The mixture is diluted with water and the steroid extracted with chloroform. The chloroform extract is washed with water, dried over sodium sulfate and the solvent removed in vacuo. The crude residue (about 197 mg), after one recrystallization from acetone-hexane, melts at about 192-194".

Similarly, but holding the temperature at 0 for 6 hours, chloro A pregnadiene 21 ol 3,11, 20-trione 3,20-bis-ethylene ketal 21-acetate yields 9w chloro A pregnadiene 115,21 diol 3,20 dione 3,20-bis-ethylene ketal (XII).

EXAMPLE 6 9a-fluor0-A -pregnadiene-11B,21-di0l-3,20-di0ne (IX) is obtained 9a-fluoro-A -pregnadiene-11;3,21-diol-3,20-'

dione.

Similarly 9oz chloro A5116 pregnadiene 1118,21 diol-3,20-dione 3,20-bis-ethylene ketal yields 9a-chloro- A -pregnadiene-11p,21-dio1-3,20-dione (X).

21-ol-3,l1,20-trione in 0.5 ml. of pyridine and 0.5 m1.

of acetic anhydride is allowed to stand overnight at room temperature. vacuo, the residue is crystallized from acetonerhexane. It represents the 21-acetate.

Similarly, by substituting 9a-fiuoro-A -pregnadiene- 1113,21 diol 3,20 dione, 9a chloro A pregnadiene 21 o1 3,11,20 trione and 90:. chloro A pregnadiene-11fl,21-dio1-3,20-dione for the 9a-fluoro- A -pregnadiene-21-ol-3,11,20-trione in the procedure of Example 7, the respective 21-acetates are formed. Furthermore, if another acylating agent such as propionic anhydride or benzoyl chloride is substituted for the acetic anhydride in Example 7, the corresponding 21-ester is produced.

The invention may be otherwise variously embodied within the scope of the appended claims.

What is claimed is:

1. 9a halo 1 pregnadiene 21 01'- 7 3,-11,20-

trione.

2. 9a fluoro A4116 pregnadiene 21 01' 3,11,20- trione.

3. 9a halo A4,16 pregnadiene 1113,21 did-3,20- dione.

4. 9a. fluoro M pregnadiene 1118,21 diol 3, ZO-dione.

After removal of the reagents in 5. A-compound of thegeneral formula.

(IIHIOY vvherein R ishydrogen, R is Bv-hydroxy andtogether R and R" is keto, X is halogen, and'Y is selected from the group consisting of hydrogen and the acyl radical of ahydrocarbon carboxylic acid having less than ten carbon atoms.

References Cited in the file of this patent UNITED STATES PATENTS Herzog Sept. 30, 1958 OTHER REFERENCES Allen: I.A.C.S., vol. 77, pages 1028-1032, February 20,1955.

Allen: J.A.C.S., vol. 76, pages 5,1954. Fried: J.A.C.S., vol. 76, pages 1455-1456. March 5, 1954.

6116- 6119, December 

5. A COMPOUND OF THE GENERAL FORMULA 